This application addresses the program announcement for Mechanisms Mediating Osteoarthritis in Aging PA-12-018. Our focus is on understanding the role of mechanobiological factors in the onset and progression of osteoarthritis in a mouse model with compromised tissue properties. Osteoarthritis (OA) reduces mobility and function by altering the structure and property of the affected joint, particularly of the cartilage and bone. Both biological and mechanical factors have been linked to the development and onset of OA, including mechanical loading. We have developed non-invasive in vivo mouse loading model of the mouse knee that recapitulates clinical OA-like features temporally and anatomically. Combining this model with transgenic mice, we plan to investigate the role of altered cartilage composition in the development of OA using transgenic mice that spontaneously develop early OA-like features at 3 months of age. We hypothesize that controlled mechanical loading of the knee joints in mice with abnormal cartilage matrix composition and properties will result in enhanced OA-like changes in articular cartilage and peri-articular bone compared to their wild type littermates. To determine whether loading expedites the development of OA-like changes, we will compare mice with type XI haploinsufficiency (cho/+ mice) to wild-type controls at 3 and 6 months of age and apply 1, 2 and 6 weeks of loading. Changes in cartilage, bone and joint mobility will be assessed by histology, microcomputed tomography, immunohistochemistry, RT-qPCR, atomic force microscopy, and kinematic analysis. This loading model provides an opportunity to study the response to mechanical stimuli without concurrent joint trauma to better understand mechanical factors contributing to OA and the interaction of biological and mechanical factors in joint degeneration.
Osteoarthritis (OA) is the leading cause of disability in adults. The proposed in vivo mechanical loading model will allow us to understand the temporal progression of cartilage and bone changes in the development of OA with loading. Combining loading with biological models that alter tissue properties will provide better understanding of mechanical and biological mechanisms underlying the disease.
|Adebayo, Olufunmilayo O; Ko, Frank C; Goldring, Steven R et al. (2017) Kinematics of meniscal- and ACL-transected mouse knees during controlled tibial compressive loading captured using roentgen stereophotogrammetry. J Orthop Res 35:353-360|
|Adebayo, O O; Ko, F C; Wan, P T et al. (2017) Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice. Osteoarthritis Cartilage 25:2108-2118|
|Kelly, Natalie H; Schimenti, John C; Ross, F Patrick et al. (2016) Transcriptional profiling of cortical versus cancellous bone from mechanically-loaded murine tibiae reveals differential gene expression. Bone 86:22-9|
|Ko, Frank C; Dragomir, Cecilia L; Plumb, Darren A et al. (2016) Progressive cell-mediated changes in articular cartilage and bone in mice are initiated by a single session of controlled cyclic compressive loading. J Orthop Res 34:1941-1949|
|Holyoak, Derek T; Tian, Ye F; van der Meulen, Marjolein C H et al. (2016) Osteoarthritis: Pathology, Mouse Models, and Nanoparticle Injectable Systems for Targeted Treatment. Ann Biomed Eng 44:2062-75|
|Christiansen, B A; Guilak, F; Lockwood, K A et al. (2015) Non-invasive mouse models of post-traumatic osteoarthritis. Osteoarthritis Cartilage 23:1627-38|
|Jepsen, Karl J; Silva, Matthew J; Vashishth, Deepak et al. (2015) Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. J Bone Miner Res 30:951-66|